This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall lung cancer mortality rate is the highest among all cancers. Therefore, the development of effective therapies is urgent in order to conquer this disease. We recently demonstrated successful cancer tissue-targeted gene therapy using interferon (IFN) [unreadable]beta expressing adult stem cells prepared from human umbilical cord matrix (UCMSC). Our stem cell-based gene therapy markedly attenuated lung metastasized cancer growth in human lung cancer mouse models. Moreover, our stem cells are easily prepared without ethical issues and have been shown to generate no stem cell-induced tumor formation. These observations suggest that UCMSC are a safe and useful tool for cancer-targeted gene therapy. In addition, we recently discovered that cardiovascular hormone receptor (angiotensin II type 2 receptor (AT2) gene) over-expression through biodegradable nanoparticle vector induces cancer cell-specific cell death in several human lung cancer cell lines. AT2 over-expression also induced cell death in cancer stem cells in culture. A combination therapy with IFN-beta and AT2 over-expression synergistically attenuated lung cancer cell growth. The primary objective of our research is to develop a practical gene therapy for lung adenocarcinoma by merging stem cell biology and a nanotechnology-based gene-delivery system. The overall hypothesis in this proposal is that a combination therapy with IFN-beta-expressing UCMSC and AT2 gene encapsulated nanoparticles is a powerful cancer-targeted gene therapy for lung adenocarcinoma. Our treatment strategy is significantly better than existing therapeutic strategies since we anticipate a better cancer attenuation effects but fewer side effects. Therefore, this study is valuable and has high potential for future human application.